Editors' ChoiceMetabolism

Fickle Phenylalanine Mutation

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Sci. Signal.  30 Mar 2010:
Vol. 3, Issue 115, pp. ec95
DOI: 10.1126/scisignal.3115ec95

The hormone leptin is secreted from adipose tissue and regulates food intake and energy use through its effects on the brain. Lack of leptin signaling through its receptor causes obesity and diabetes in mice and is associated with obesity in humans as well. The leptin receptor signals in part through a set of three tyrosine residues that become phosphorylated after leptin binding. Their effects are complex: The phosphorylated residues are bound by other signaling proteins, and one mediates signaling through the JAK2 protein kinase and STAT (signal transducer and activator of transcription) transcription factors and another, Tyr985, appears to mediate both positive and negative signals and is proposed to provide autoinhibition to the receptor. Tyr985 is bound by the SOCS3 protein, which inhibits activation of STAT3, and also by the protein phosphatase SHP2 (SH2-containing protein tyrosine phosphatase 2), which can antagonize JAK-STAT signaling but also appears to lead to increased leptin signaling through the protein kinase ERK (extracellular signal–regulated kinase). You et al. studied mice engineered to have Tyr985 converted to phenylalanine to prevent its phosphorylation. When they were young, the resultant animals were leaner than control animals and showed increased responses to leptin. The males showed decreased food intake and increased energy expenditure. However, as the animals aged, the opposite was true. As they got older, the mutant animals ate more than controls and expended less energy; moreover, the older animals were resistant to leptin. Obesity induced by a diet high in fat was also greater in the older mutant mice than in control animals. The authors propose that Tyr985 may be important for normal adjustment of metabolic control as mice age. Furthermore, signaling through Tyr985 may be relevant for understanding and treating the propensity of humans toward age-related obesity and obesity induced by overconsumption of dietary fats.

J. You, Y. Yu, L. Jiang, W. Li, X. Yu, L. Gonzalez, G. Yang, Z. Ke, W. Li, C. Li, Y. Liu, Signaling through Tyr985 of leptin receptor as an age/diet-dependent switch in the regulation of energy balance. Mol. Cell. Biol. 30, 1650–1659 (2010). [Abstract] [Full Text]